We tested the hypothesis that a humanized non-depleting anti-CD4 antibody (OKT4acdr3) would prolong adenoviral-mediated gene expression in rhesus lungs. We treated rhesus macaques with 12 mg/kg OKT4a IV daily on days -1 to day +11. On day 0, animals were given 5 x 1010 pfu of AdCMVLacZ into the lung. A subgroup was continued on a secondary gene transfer protocol by administering AdCMVLacZ into the other lung. There was less inflammation and greater gene transfer in anti-CD4 treated animals. Secondary gene transfer was not efficiently accomplished in either group. OKT4acdr3 blocked T-cell activation to adenovirus and lacZ and prolonged gene expression. OKT4cdr3 did not attenuate B-cell responses. Possibly OKT4a specifically blocked the generation of a TH1 response. Studies using anti-CD4 antibodies in rodents have been performed in naive animals. All our monkeys had baseline non-neutralizing anti-adenoviral antibodies. Thus, another hypothesis is that low numbers of memory B-cells can proliferate in the absence of CD4 dependent help. Since most patients have anti-adenoviral antibodies, we must discern the correct hypothesis for repetitive gene transfer to be developed. FUNDING Cystic Fibrosis Foundation, J. Kolls, PI, $150,000 PUBLICATIONS None